tbuckley/cabot-search huggingface dataset:
Age associated mutations in cutaneous squamous cell carcinomas (CSCC).
Authors: Priyanka Kumar, Danielle Brazel, Hung Doan, Justin Tyler Moyers
Journal: Journal of Clinical Oncology (2022)

e21592 Background: Cutaneous squamous cell carcinoma is the second most common skin cancer globally. However, advanced or metastatic disease is rare and is primarily a disease of the elderly or immunocompromised. The relationship between age and the presence and frequency of poor prognostic indicators (TP53 or TERT promoter mutations) and therapeutic targets (ERBB4) is unknown. Methods: We queried the American Association for Cancer Research (AACR) Project GENIE for cutaneous squamous carcinomas accessed through cBioPortal. We gathered genomic alterations and demographic data by age groups at time of tumor sequencing (&lt; 65years, 66-80 years, &gt; 81 years). Genomic alterations were assessed for function by OncoKB. Descriptive variables were presented as frequencies and compared by Chi squared method. Results: Among 1,025 non-melanoma skin cancer samples, 285 total CSCC samples were identified within the database. By age groups, 104 (36%) samples were from those 65 or younger, 127 (45%) in those 66-80 years, and 54 (19%) in those older than 80 years. Prevalence of TP53 mutations increased with age, 72% in &lt; 65, 88% in 66-80, and 93% in &gt; 80 (p &lt; 0.001). Nearly all TP53 mutations were functional (96%; 228/237). ROS1 mutations also significantly increased in prevalence with older age, 27% in those &lt; 65, 37% in 66-80, and 48% in &gt; 80, respectively (p = 0.03). However, all ROS1 alterations were variants of unknown significance (VUS). TERT alterations also increased in frequency with more advanced age, with 32% in those &lt; 65, 45% in 66-80, and 46% in &gt; 80 (p = 0.078). ERBB4 alterations also increased in prevalence with age, 28% in those &lt; 65, 30% in 66-80, 33% in &gt; 80 groups (p = 0.71), however only 9/130 (6.9%) were known oncogenic alterations. Conclusions: Tumor suppressor genes (such as TP53, TERT, KMT2D, NOTCH1, NOTCH2, and FAT1) were frequently altered in CSCC among the AACR GENIE population, while actionable mutations and gain of function driver mutations (such as ERBB4) were infrequent.
Comparison of surgical resection combined with chemotherapy and palliative chemotherapy for synchronous hepatic metastases from gastric cancer.
Authors: Pingyuan Yu, Yu Pengfei, Zhihui Jiang, Yang Cao, Zeyao Ye, Tengjiao Chai, Yian Du
Journal: Journal of Clinical Oncology (2022)

e16041 Background: Hepatic metastases of gastric cancer(HMGC) are an important factor affecting the prognosis of gastric cancer patients, and 3-14% of gastric cancer cases were diagnosed with synchronous hepatic metastases of gastric cancer (SHMGC). However, there remains much unidentified about the therapy effect of surgical resection on SHMGC. Here, we investigated the associations of surgical resection with the overall survival of SHMGC, which might develop more effective therapy strategies for patients of HMGC. Methods: Patients diagnosed with SHMGC from January 2010 to December 2015 were selected in the study. Kaplan-Meier analysis and multivariable analysis based on the Cox proportional hazards model were performed to compare the effects of surgical resection (including gastrectomy and metastasectomy) combined with chemotherapy (surgical resection group, SR group) and palliative chemotherapy (palliative chemotherapy group, PC group) on survival. Results: A total of 132 patients were enrolled in this study. Overall, 57 (43.2%) were treated with surgical resection/chemotherapy and 75 (56.8%) palliative chemotherapy. Overall survival (OS) was significantly prolonged in the SR group compared with the PC group (33.6 vs. 12.4 months, P &lt; 0.001). In the SR group, the R0 resection (68.4%, 39/57) contributed to markedly prolonged OS compared with the non-R0 resection subgroup (45.1 vs. 13.5 months, P &lt; 0.001). Surgical resection and single hepatic metastasis were independent predictors of OS in multivariate analysis with hazard ratio (HR) of 0.453 (95% confidence interval [CI] 0.276-0.813, p = 0.009) and 0.540 (95%CI 0.315-0.796, p = 0.043), respectively. Conclusions: For patients with synchronous hepatic metastases of gastric cancer, radical surgical resection combined with appropriate chemotherapy may be more beneficial than palliative chemotherapy. Moreover, single hepatic metastasis might achieve better survival after aggressive surgical resection.
Effects of prophylactic high and low doses of corticosteroid on the efficacy of immune checkpoint blockade in murine hepatocellular carcinoma models.
Authors: Ying-Chun Shen, Ching-Ping Yeh, Lu Jin, Nai-Wen Chang, Chia-Lang Hsu, Da-Liang Ou, Ching-Liang Chu, Ann-Lii Cheng
Journal: Journal of Clinical Oncology (2022)

e14596 Background: Immune-related adverse events (irAEs) are major hurdle to immune checkpoint blockade (ICB). Corticosteroid (CS) is effective in controlling the majority of irAEs. Although recent studies suggested CS use does not jeopardize the anti-tumor efficacy of ICB, prophylactic use of CS remains prohibited with the concerns of attenuating efficacy of ICB. This study aimed to investigate the effects of CS premedication on the efficacy of ICB in murine hepatocellular carcinoma models. Methods: Anti-mCTLA-4 (9D9C, BMS) and anti-mPD-1 antibodies (4H2, ONO) were intraperitoneally (ip) administered to tumor-bearing mice (subcutaneous Hepa 1-6 model and orthotopic BNL 1MEA.7R.1 model) with or without dexamethasone (DEXA) premedication (10 and 200 μg, equivalent to minimal anti-inflammatory dosage and pulse therapy in human, respectively). Efficacy of ICB was evaluated as tumor shrinkage. Tumor-infiltrating lymphocytes (TILs) were isolated for single cell RNA-sequencing and effector function analysis through flow cytometry. Results: In the subcutaneous model, all tumors treated with ICB alone (N=7) or ICB plus DEXA 10 μg (N=5) completely regressed, but 1 out of 7 tumors treated with ICB plus DEXA 200 μg escaped. However, the tumor growth was not significantly different between groups ( P-value &gt;0.05, multiple Mann-Whitney test). In the orthotopic model (N=5/group), the mean (± standard error) tumor weights on day 21 after tumor implantation for isotype control, ICB, ICB plus DEXA 10 μg and ICB plus DEXA 200 μg were 2.45 (± 0.54), 0.73 (± 0.18), 0.98 (± 0.65), and 0.69 (± 0.17) grams, respectively ( P-value &gt;0.05, comparing ICB plus DEXA 10 or 200 μg with ICB). At transcriptomic level, premedication with either dosage of DEXA significantly reduced the percentage of effector memory cells and increased the percentage of exhausted effector cells in the CD8 TIL population, which appeared to counterbalance the effects of ICB. However, at protein level, premedication of DEXA 10 or 200 μg did not reduce the interferon-γ or granzyme B production of CD8 TILs in both models (Table). Conclusions: CS premedication did not attenuate the efficacy of ICB. Our study provides the scientific basis to evaluate the potential of prophylactic CS in preventing ICB-induced irAEs in clinical studies.[Table: see text]
Molecular analyses of metastatic collecting ducts renal cell carcinoma from the phase 2 prospective trial of cabozantinib as first-line treatment (BONSAI trial Meeturo 2).
Authors: Katia Todoerti, Pierangela Sepe, Devecchi Andrea, Adele Busico, Luca Agnelli, Federica Perrone, Chiara Gargiuli, Matteo Dugo, Loris De Cecco, Melanie Claps, Giuseppe Fotia, Valentina Guadalupi, Elena Verzoni, Giuseppe Procopio
Journal: Journal of Clinical Oncology (2022)

e16507 Background: The phase II BONSAI trial ( n = 25 ; NCT 03354884) met the primary endpoint demonstrating activity of cabozantinib in untreated metastatic collecting ducts carcinoma (mCDC), a rare and biologically poorly characterized disease. Here we report on molecular analyses of baseline tissue samples. Methods: Formalin-fixed paraffin-embedded (FFPE) samples from 18 mCDC patients enrolled in BONSAI were sequenced by TruSeq RNA Exome kit (Illumina). The data were mapped and quantified using STAR and htseq, respectively. Globaltest and edgeR packages in R were used to assess the correlation between transcriptional profiles and survival data. Nineteen samples underwent DNA Sequencing with the Oncomine Comprehensive Assay Plus (ThermoFisher Scientific). The reads were aligned to the human genome reference (hg19) and analyzed with Opencravat and IonReporter software. Germline variants were excluded based on 1000 Genomes, GnomAd and Exac databases, and Clinical annotation of somatic variants was performed using ClinVar. Results: The global expression levels of thirty-one genes have been found significantly associated with overall survival (OS). The natural grouping of the 18 tumor samples based on the 31-gene signature identified a main group of 11 cases, showing global higher expression levels in 22 out of the 31 genes. This group displayed overall a significant higher OS rate in comparison to the remaining 7 patients, carrying opposite expression trend and mostly undergoing to disease progression. The identified signature was enriched in biological processes like cell junction, cytoskeleton organization and methylation. FOS oncogene was among the 9 genes negatively associated to OS, showing common higher expression in the poorer survival rate group. Furthermore, a 22-gene signature was found significantly associated with progression-free survival (PFS), involving mainly genes associated to cell cycle regulation or recognized as components of Golgi apparatus. Only three genes were globally up-regulated in the group of 9 patients characterized by shorter PFS. Finally, heterogeneous pattern of somatic mutations was identified in 19 tumor samples, with at least 8 genes recurrently affected in more than three patients. Notably, mutated genes were mostly involved in DNA repair and chromatin modification processes. Conclusions: Our findings for the first time define specific molecular signatures that differentiate therapy-specific outcomes in first-line mCDC, warranting further investigation of their involvement in the tumor biology. Clinical trial information: NCT 03354884.
Prognostic impact of bone metastasis in patients with metastatic urothelial carcinoma (mUC) treated with durvalumab (D) with or without tremelimumab (T) in the DANUBE study.
Authors: Carlos Stecca, Osama Abdeljalil, Cindy Lu, Han Zhang, Erik T. Goluboff, Srikala S. Sridhar
Journal: Journal of Clinical Oncology (2022)

4564 Background: In mUC, bone metastases (BM) are associated with significant morbidity and mortality, but their independent impact on outcomes is not well established, especially in the current era of immune checkpoint inhibitors (ICIs). This post-hoc analysis assessed the impact of BM, as well as PD-L1 status (within the same BM category) on outcomes of patients with mUC treated with ICIs. Data was derived from the Phase 3 DANUBE study, which compared D, D+T, and standard chemotherapy (SoC). Methods: Patient characteristics, disease characteristics, treatments, and outcomes were collected. Patients were categorized as having BM or no BM. Outcomes included median overall survival (OS) and median progression-free survival (PFS) (in months [mo]), estimated by the Kaplan-Meier method. PD-L1 expression was assessed using the VENTANA PD-L1 (SP263) Assay. Results: Overall, 1032 patients were included; 266 had BM (D, 80; D+T, 97; SoC, 89), and 766 had no BM (D, 262; D+T, 249; SoC, 255). Among all patients, those with BM had a lower OS than those with no BM (HR, 1.67; 95% CI, 1.43-1.92; nominal P&lt; 0.0001) when controlling for cisplatin eligibility, PD-L1 expression, presence of visceral metastases, and treatment. Similarly, patients with BM had lower PFS compared to those without BM (HR, 1.52; 95% CI, 1.30-1.75; nominal P&lt; 0.0001) Within each treatment arm, median OS was lower for patients with BM compared to patients with no BM for all patients, regardless of PD-L1 status (Table). Patients with BM and PD-L1–high expression, treated with either D or D+T, had numerically higher median OS compared to those with PD-L1 low; this difference was also seen in patients with no BM. In contrast, there was no difference in median OS, for BM or no BM, based on PD-L1 expression for patients treated with SoC (Table). Conclusions: In this post-hoc analysis, presence of BM was significantly and consistently associated with worse outcomes in patients with mUC across all treatment arms of the DANUBE study. PD-L1–high expression was associated with higher median OS in patients treated with D or D+T, regardless of presence of BM. These data reinforce the negative prognostic impact of BM in mUC and the role for PD-L1 expression in predicting benefit for patients treated with ICIs. Funding: AstraZeneca. Clinical trial information: NCT02516241. [Table: see text]
Meta-analysis and systematic review of the role of preemptive oral antibiotics and topical vitamin K for acneiform rash induced by EGFR-targeted therapies.
Authors: Andre Bacellar Costa Lima, Andre Deeke Sasse
Journal: Journal of Clinical Oncology (2022)

e13646 Background: Acneiform rash (AR) is the most frequent adverse event associated with epidermal growth factor receptor (EGFR) inhibitors, which are widely used to fight solid tumors. Multiple trials studied prophylactic measures to help prevent the incidence and severity of this skin toxicity. The aim of this systematic review and meta-analysis (MA) was to analyze the clinical efficacy of the two most studied prevention strategies to mitigate the severity of skin rash induced by EGFR inhibitors. We sought to understand the current role of oral antibiotics and topical vitamin K in this scenario. Methods: A wide search through electronic databases and congress abstracts was performed. Studies with control groups reporting the pre-emptive role of both oral antibiotics and topical vitamin K were selected for two separate MA. Overall incidence and severity of AR were the analyzed dichotomous outcomes. Results: Fourteen studies (n=1085) were included in the antibiotics MA. Antibiotics prevented both moderate to severe (OR 0.38; CI 95% 0.24-0.60) and all-grade AR (OR 0.55; CI 95% 0.39-0.78). Four studies (n=507) were selected for the vitamin K MA. No benefit in the prevention of grade ≥ 2 AR was observed for this topic agent in the prophylactic setting (OR 1.21; CI 95% 0.79-1.85). Conclusions: There is still need to seek more efficacious ways to manage skin toxicities associated with EGFR inhibitors since this can impair quality of life and cancer treatment adherence. The use of oral antibiotics should be more encouraged as a prophylactic measure in the current guidelines.
Detection of homologous recombination deficiency (HRD) in cell-free DNA (cfDNA) using an amplicon-based next-generation sequencing (NGS) assay.
Authors: Jonathan Poh, Harvinder Kaur, Jia Min Ho, Yukti Choudhury, Min-Han Tan
Journal: Journal of Clinical Oncology (2022)

3042 Background: Homologous recombination (HR) deficiency is characterized by tumor genomic instability, often due to alterations in BRCA1/2 and other HR-related genes. HRD predicts sensitivity to PARP inhibitors (PARPi) in prostate, ovarian and breast cancers. For the subset of cancers that have genomic instability without detectable alterations in HR genes, profiling biomarkers of HRD such as loss of heterozygosity (LOH) could identify additional HRD positive (HRD+) patients that may benefit from PARPi. Here, we present a novel cfDNA NGS assay that can detect tumor LOH non-invasively to improve assessment of HRD+ status. Methods: An amplicon-based HRD NGS assay covering &gt; 1000 SNPs was developed to detect LOH both globally and on the gene level in cfDNA. Analytical validation was done using LOH+ BRCA-mutant cell lines in limiting dilution admixtures. Clinical performance was assessed by benchmarking findings from 46 tumor tissue DNA samples against results from an orthogonal NGS-based genomic scarring assay. Clinical utility of the HRD assay was evaluated in 75 cfDNA samples, including 72% (54/75) from BRCA-associated cancers (36 breast, 12 prostate, 4 ovarian, 2 pancreatic) and 28% from other cancer types. All cfDNA samples were previously clinically tested by an NGS assay that included BRCA1/2 (LiquidHALLMARK). A subset of cfDNA samples identified as HRD+ were further assessed for alterations in 26 key HR genes ( ARID1A, ATM, ATR, ATRX, BAP1, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCA, FANCC, FANCG, FANCL, MRE11, NBN, PALB2, PTEN, RAD51, RAD51B, RAD51C, RAD51D, RAD54L, and XRCC2). Results: In analytical validation, the assay could detect HRD in admixtures with as low as 18% tumor fraction. In tissue samples, overall concordance of HRD status with the orthogonal test was 91.3% (42/46), with a positive percent agreement of 94.4% (34/36) and negative percent agreement of 80.0% (8/10). In cfDNA, 26.7% (20/75) of samples were HRD+, including 29.6% of BRCA-associated cancers (16/54; 12 breast, 2 prostate, 1 ovarian, and 1 pancreatic) and 19.1% (4/21) of other cancer types. In the three HRD+ breast cancers with pathogenic BRCA mutations, the assay also identified BRCA-specific LOH. Nine HRD+ breast cancers (two BRCA+ and seven BRCA-) were further analyzed for alterations in 26 HR genes. Of the two BRCA+ HRD+ breast cancers, one harbored an additional PTEN loss-of-function (LOF) mutation. Of the seven BRCA- HRD+ breast cancers, one harbored biallelic PALB2 and CDK12 LOF mutations, while another harbored a CDK12 LOF mutation. Conclusions: LOH detection in cfDNA provides additional diagnostic yield of HRD+ status in multiple cancer types, even in the absence of pathogenic HR gene alterations. Further clinical studies to evaluate the utility of HRD detection in cfDNA using LOH and to determine concordance with tumor tissue are ongoing.
Safety and efficacy of mitoxantrone hydrochloride liposome in patients with platinum-refractory or platinum-resistant ovarian cancer: A prospective, multicenter, open-label, single-arm, phase Ib clinical trial.
Authors: Yu Huang, Rong Li, Li Guiling, Yanlin Luo, Zhijun Yang, Ge Lou, Weiwei Ouyang, Rong Xie, Wuxia Luo, Lixin Chen, Qi Zhou
Journal: Journal of Clinical Oncology (2022)

5550 Background: Platinum-refractory or platinum-resistant ovarian cancer remains unmet medical need with an unfavorable prognosis. Its treatment options are limited and sequentially with multiple single-agent regimens or bevacizumab plus single-agent regimens are recommended. Mitoxantrone hydrochloride liposome (PLM60) is the first approved mitoxantrone nano-drug, which has shown favorable pharmacokinetic characteristics with long circulation and high cumulation in tumor tissue, thus has a promising anti-tumor activity. This trial aimed to explore the efficacy and safety of PLM60 in patients with platinum-refractory or platinum-resistant ovarian cancer. Methods: In this multi-center, open-label, single arm study, patients with histologically confirmed, epithelial ovarian, fallopian tube, or primary peritoneal carcinoma, either platinum-refractory or platinum-resistant, with at least one measurable lesion were recruited. PLM60 20 mg/m 2 was administered on day 1 of each 21-day cycle for up to 8 cycles treatment or until disease progression or intolerable toxicities. The primary endpoint was safety, adverse events were graded according to CTCAE 5.0. Second endpoint included overall response rate (ORR), duration of response (DoR), disease control rate (DCR), progression free survival (PFS) and overall survival (OS) as per RECIST 1.1. Results: 47 eligible patients with a median age of 54 years (range, 35-67) were treated in 7 institutions in China, including 15 platinum-refractory patients and 32 platinum-resistant patients. 32 (68.1%) of 47 patients received at least 3 prior lines of therapy. Treatment related adverse events (TRAEs) of any grade occurred in 45 (95.7%) of 47 patients, in which 31 (66.0%) were ≥ grade 3. The most common ≥ grade 3 TRAEs (incidence ≥10%) were leucopenia (51.1%), neutropenia (40.4%), anemia (19.1%), lymphocytopenia (17.0%) and thrombocytopenia (17.0%). At the cut-off data of October 31 2021, 39 patients were evaluable for response. ORR was 17.9% (7/39, 95% CI:7.5-33.5%, 7 PRs) and DCR was 56.4% (22/39, 95% CI:39.6-72.2%, 15 SDs). Among 21 platinum-resistant patients with ≥3 prior lines, the median DoR was 4.6 month, 2 responders had a DoR of &gt; 6 months. The ORR and DCR of this cohort were 28.6% (6/21, 95% CI: 11.3-52.2%, 6 PRs) and 61.9% (13/21, 95% CI: 38.4-81.9%, 7 SDs), respectively. Median PFS was 3.6 month (95% CI 1.4-4.6), OS data was not mature. Objective response was not observed in platinum-refractory patients. Conclusions: PLM60 had an encouraging efficacy especially in platinum-resistant patients who had received at least 3 prior lines with tolerable safety profiles. Clinical trial information: NCT04718376.
Breast cancer after reduction mammoplasty: A population-based analysis of incidence, treatment, and screening patterns.
Authors: Ashley Drohan, May Lynn Quan, Dale Birdsell, Shiying Kong, Yuan Xu
Journal: Journal of Clinical Oncology (2022)

e18785 Background: The incidence of breast cancer after reduction mammoplasty has been demonstrated to be lower than the general population in several large registry trials performed in primarily European populations; North American data is lacking. Tissue rearrangement during reduction mammoplasty may lead to abnormal breast imaging results postoperatively resulting in more challenging screening.The purpose of this study was to describe the incidence and treatment of breast cancer after reduction mammoplasty in a more contemporary Canadian population, and to better understand the use of breast cancer screening modalities in these patients. Methods: This population-based retrospective analysis utilized the Discharge Abstract Database held by the Canadian Institute for Health Information (CIHI) and the National Ambulatory Care Reporting System (NACRS) to identify all women 20 or older who underwent reduction mammoplasty in Alberta, Canada between 2003 and 2007. The incidence and treatment of breast cancer was compared among patients who underwent reduction mammoplasty and age-sex matched controls in Alberta. Imaging utilization post mammoplasty, including use of mammography, ultrasound and breast biopsy was also compared between these two groups. Results: A total of 8,021 patients over 20 years old underwent reduction mammoplasty during the study period. Patients were followed for an average of 12.6 years. Most women (6,417, 80%) underwent reduction mammoplasty surgery between the ages of 20-50. Compared to controls, women who underwent reduction mammoplasty had more comorbidities (Charlson Comorbidities &gt; 1: 5.2% vs 4.2% controls, p &lt; 0.0001). Overall, 89 (1.1%) patients who underwent reduction mammoplasty developed breast cancer after surgery, compared to 453 (1.9%) controls (p &lt; 0.0001). Among patients diagnosed with breast cancer, there was no difference in patient characteristics, tumor size, histology and grade between the two groups. Fewer patients presented with metastatic disease after reduction mammoplasty (0% vs 5.1%, p = 0.043). The surgical treatment differed between groups; patients who underwent reduction mammoplasty were significantly more likely to undergo mastectomy for breast cancer (41.6% vs 1.5%, p &lt; 0.0001). Women who underwent reduction were more likely to undergo mammography (66.7% vs 58.7%, p &lt; 0.001), ultrasound (29.2% vs 26.2%, p &lt; 0.0001) and biopsy for benign disease (7.2% vs 6%, p = 0.0001) compared to controls. Conclusions: Despite an increased frequency of breast cancer screening, the incidence of breast cancer is lower after reduction mammoplasty compared to women who did not undergo breast reduction. After a diagnosis of breast cancer, surgical treatment patterns differ between groups despite similarities in tumor characteristics, whereby mastectomy is more common in those who have undergone breast reduction.